The Bethesda Handbook of Clinical Oncology, 4th Ed.

30

Hematopoietic Cell Transplantation

Abraham S. Kanate, Michael Craig, and Richard W. Childs

The effective therapeutic implementation of hematopoietic cell transplantation (HCT) required the concerted efforts of several prominent investigators spanning the entire 20th century. Seminal work done predominantly on murine models identified the cellular basis of hematopoiesis and raised the possibility of human HCT in the first half of the 20th century. The latter half witnessed the successful, albeit with early setbacks and pessimism, therapeutic application of human HCT. For his pioneering efforts in the field, Dr. E. Donnall Thomas received the Nobel Prize in Physiology or Medicine in 1990. Currently it is estimated that over 50,000 patients undergo HCT annually worldwide that includes both autologous (auto-HCT) and allogeneic (allo-HCT).

HCT is an effective therapeutic option for patients with a wide range of malignant and benign conditions. Apart from matched related donor (MRD) allo-HCT and auto-HCT, patients may be offered allografts from unrelated donors (URD), HLA-mismatched, cord blood, or haploidentical donors. In recent years the application of HCT has broadened with the advent of reduced intensity conditioning (RIC) regimens. Although HCT may be associated with significant morbidity and mortality, advances in supportive care, human leukocyte antigen (HLA) typing, prevention, and treatment of graft-versus-host disease (GVHD), and better management of complications have led to improved outcomes. A brief overview of autologous and allogeneic HCT is provided in this chapter, along with a discussion of the complications and their management.

HEMATOPOIETIC STEM CELLS

Hematopoietic stem cells (HSCs) reside within the bone marrow space (niche) in close association with stromal cells and extracellular matrix proteins and are capable of producing progenitor cells that can reconstitute the hematopoietic system including lymphoid, erythroid, and myeloid cell lines. True HSC are characterized by their unlimited self-renewal capacity, pluripotency, quiescence, and extensive proliferative capacity. While committed progenitor cells may retain some of the HSC properties and may repopulate the hematopoietic system, they lack self-renewal capacity. In humans, the HSC immunophenotype is characterized as CD34+, CD38-, Thy-1low and lacking lineage-specific markers, although a population of CD34- stem cells has also been described. Considering the abundance of hematopoietic cells, true HSCs are relatively rare and constitute only 1 in 10,000 bone marrow cells. A unique property of the infused HSC is the ability to migrate and occupy bone marrow niches by virtue of surface adhesion molecules, chemokines, and their receptors. The number of CD34+ cells in the graft product has important ramifications on post-HCT outcomes and lower CD34+ cell dose can be associated with a higher risk of graft failure, delayed engraftment and hematopoietic recovery, and nonrelapse mortality (NRM).

STEM CELL SOURCES

Bone Marrow

Originally bone marrow was considered the sole source of acquiring HSCs for both autologous and allogeneic transplantation. Bone marrow harvesting is the repeated aspiration of the marrow from the posterior iliac crest usually under general anesthesia to obtain the graft. The goal is to obtain ≥2 × 108/kg recipient body weight of mononuclear cells to allow safe engraftment. The maximum volume of marrow that may be safely removed at a given time is 20 mL/kg donor weight. The harvesting procedure is very well tolerated and the most common side effect is self-limiting local pain. Other adverse effects may include neuropathy, infection, and anemia (autologous red cell transfusion is considered in many centers). HCT with peripheral blood progenitor cells (PBPC) has largely replaced marrow-derived HSCs as the choice of cells for almost all auto-HCT and majority of the allo-HCT in adult patients. However, marrow remains the chief source of HSCs in pediatric patients and in some adults with nonmalignant hematologic disorders such as aplastic anemia.

Peripheral Blood

Growth factors such as granulocyte colony-stimulating factor (G-CSF) are used to “mobilize” or increase the number of HSCs and progenitor cells in the peripheral blood, which are collected by apheresis. The minimum goal of PBPC collection is 2 × 106/kg recipient body weight of CD34+ cells. The PBPC collection is very safe with no long-term adverse effects to the donor. The administration of growth factors to healthy donors may produce minor bone pain, with splenic rupture and myocardial infraction being extremely rare but more significant complications. Plerixafor is a chemokine receptor antagonist against CXCR4, which mobilizes HSC and is currently approved in combination with G-CSF prior to auto-HCT in lymphoma and myeloma patients who are often difficult to mobilize with G-CSF alone. In the setting of auto-HCT chemotherapy is sometimes used prior to G-CSF mobilization to obtain additional antineoplastic effects and the postchemotherapy recovery phase improves the PBPC yield.

PBPC grafts result in more rapid engraftment and hematopoietic recovery. Based on existing evidence PBPC is preferred over marrow HSCs in auto-HCT. It is more controversial in the setting of allo-HCT. Due to the 10- to 20-fold higher T lymphocytes present in the PB product, there is concern for increased GVHD. Results of early comparative studies in MRD allo-HCT suggest earlier engraftment, similar acute GVHD and relapse rates, and increased chronic GVHD in some but not all studies with PBPC. Results of a randomized trial in URD allo-HCT suggest increased chronic GVHD with PBPC, which is offset by delayed engraftment with marrow graft and no difference in relapse or survival. Registry studies have also suggested increased chronic GVHD in patients receiving PBPC allo-HCT for severe aplastic anemia. A risk-adapted approach is warranted in choosing the ideal graft source.

Umbilical Cord Blood

HSCs can be collected from umbilical cord blood (UCB) of placenta after delivery and cryopreserved. This represents an enriched source of HSC in a relative small volume of blood in comparison with bone marrow or PBPC and is readily available upon request. The presence of immunologically naïve immune cells allow for crossing HLA barriers without increasing the risk of GVHD. Graft rejection and delayed engraftment occur more frequently owing to lower number of nucleated cells in the infusate. However, the simultaneous use of two UCB (double UCB) units from different donors has shown to improve engraftment. Higher total nucleated cell doses and better degrees of HLA match are associated with improved transplant outcomes.

Haploidentical Donors

Half-matched relative donors are a readily available source for most patients. Early studies were associated with prohibitive GVHD in T-cell replete and graft rejection and infectious complications in T-cell–depleted allografts. Recent reports with the use of T-cell–replete marrow-derived HSC administered after RIC regimen and posttransplant high-dose cyclophosphamide (Cy) to kill allo-reactive T cells that would cause GVHD have shown encouraging results. An ongoing randomized trial compares allo-HCT outcomes with double UCB and haploidentical donors.

INDICATIONS FOR TRANSPLANTATION

HCT is considered a therapeutic option in the management of several disease entities. The National Marrow Donor Program (NMDP) website, http://www.marrow.org, provides a more complete list. See Table 30.1 for common indications in adults. Some of the salient features are

■In a pediatric population (≤20 years), chief indications for auto-HCT are nonhematologic malignancies and for allo-HCT they are benign hematologic and immune system disorders (erythrocyte disorders, inherited immune system defects, congenital metabolic diseases).

■In the adult population myeloma and lymphoma are common indications for auto-HCT, while acute and chronic leukemias, myeloid neoplasms, lymphomas, myelodysplastic syndrome, and aplastic anemia are common indications for allo-HCT.

■Trends in HCT have changed over time with therapeutic advances. An important example is as follows: allo-HCT used to be the standard of care for chronic phase chronic myeloid leukemia (CML) but not so in the tyrosine kinase inhibitor era. Similarly, there are new promising results with the use of HCT for solid tumors such as renal cell carcinoma, neuroblastoma, or nonmalignant diseases such as sickle cell anemia, and autoimmune disorders.

PRETRANSPLANT EVALUATION

Prior to treatment, a thorough discussion highlighting the transplantation procedure as well as risks and benefits associated with the procedure should take place between the physician and the patient.

■HLA typing of the patient and a search for an HLA-matched donor are required if an allogeneic transplant is being considered. Donor search is initiated with siblings as first choice, followed by URDs and alternative donors (UCB and haploidentical).

■Medical history and evaluation.

•Age: Remains an important predictor of treatment-related morbidity and mortality. However, with improving supportive care, HLA typing, and use of RIC regimens, physiologic age is considered more important than chronologic age.

•Review of original diagnosis and previous treatments, including radiation.

•Concomitant medical problems.

•Current medications, important past medications, and allergies.

•Determination of current disease remission status and restaging (by imaging studies, bone marrow biopsy, flow cytometry on blood or bone marrow, lumbar puncture, tissue biopsy as warranted).

•Transfusion history and complications, as well as ABO typing and HLA antibody screening.

•Psychosocial evaluation and delineation of a caregiver.

■Physical examination.

•Thorough physical examination including evaluation of oral cavity and dentition

•Neurologic evaluation to rule out central nervous system involvement, if indicated

•Performance status evaluation

■Organ function analysis.

•Complete blood count.

•Renal function: Preferably a creatinine clearance >60 mL per minute, except in myeloma.

•Hepatic function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than twice the upper level of normal and bilirubin <2.00 μg/dL.

•Cardiac evaluation: Electrocardiogram and echocardiography or multiple-gated acquisition imaging with ejection fraction.

•Chest x-ray and pulmonary function testing, including diffusing capacity of lung for carbon monoxide and forced vital capacity.

•Scoring schemes such as the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) that can predict NRM based on patient factors may be used to risk-stratify patients.

■Infectious disease evaluation.

•Cytomegalovirus (CMV), HIV, toxoplasmosis, and hepatitis serology

•Serology for herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella zoster virus (VZV)

•Assess for prior history of invasive fungal (aspergillus) infection

■Pregnancy testing for all women of child-bearing age and consideration of referral to reproductive center for sperm banking or in vitro fertilization.

AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

The principle behind high-dose chemotherapy (HDT) is the administration of maximal tolerated doses of cytotoxic agents to maximize tumor kill and overcome relative tumor resistance, which causes prolonged and lethal cytopenias from which the patient may be rescued with the infusion of autologous progenitor cells/HSCs to reconstitute the hematopoietic system. HDT regimens typically use combinations of cytotoxic agents with nonoverlapping organ toxicities. Commonly used regimens include (a) BEAM—carmustine + etoposide + cytarabine + melphalan (lymphoma), (b) CBV—Cy + carmustine + etoposide (lymphoma), and (c) single-agent melphalan 200 mg/m2 (myeloma). HDT is considered in chemotherapy-sensitive tumors or as consolidation therapy for patients in remission (Table 30.1). Overall it is well tolerated with NRM of <5%. Typically the auto-HCT product is mobilized with G-CSF alone or in combination with either chemotherapy or the chemokine antagonist plerixafor. The mobilized PBPC is collected by apheresis and is cryopreserved viably in dimethyl sulfoxide (DMSO) and thawed just prior to infusion. Complications related to HDT and auto-HCT include:

■Rare infusional reactions may include bronchospasm, flushing, hypertension, or hypotension secondary to DMSO.

■Pancytopenia for 10 to 14 days with the predominant use of PBPC and G-CSF. Packed red cell (PRBC) and platelet transfusions may be required.

■Infectious complications—bacterial, viral, and fungal infections may manifest during the cytopenic phase but can be effectively prevented with antimicrobial prophylaxis. Late infections include Pneumocystis jiroveci and varicella requiring continued prophylaxis beyond engraftment.

■Regimen-related toxicities may be (a) acute—infusional reaction (carmustine), hemorrhagic cystitis (Cy), hypotension (etoposide) or (b) delayed—pulmonary toxicity (carmustine, total body irradiation [TBI]), sinusoidal obstruction syndrome (SOS) (TBI or alkylating agents) and myelodysplasia (TBI, alkylating agents, etoposide).

■Relapse of the primary malignancy remains a major barrier to long-term survival.

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION

Allo-HCT has progressed from an experimental treatment of last resort to standard of care therapy for several disease conditions (Table 30.1). Extensive planning and co-ordination of care is required for all transplant candidates, usually involving a network of physicians and support staff. For patients without a MRD, the NMDP is an invaluable resource for the purpose of URD allo-HCT. All physicians may perform a free initial search for an HLA-matched URD in the NMDP, which maintains a registry of about 9 million potential donors and 145,000 UCB units. As of 2013, the NMDP can search over 16 million URD and 500,000 UCB units as potential donors through its international networks.

Graft-versus-Tumor Effect

In the context of malignancies, the major therapeutic benefit of allo-HCT is the potential for the colonizing donor immune system to recognize and eradicate the malignant or abnormal stem cell clone, the so called graft-versus-tumor (GVT) effect. This immune effect is largely mediated by transplanted donor lymphocytes and is evidenced by the lower relapse rate of hematologic malignancies in patients who undergo allo-HCT than in those who undergo auto-HCT, as well as by an increased relapse rates in syngeneic (identical twin) donor or T-cell–depleted allo-HCT. Arguably the most important and direct evidence for GVT effect comes from the ability of therapeutic donor lymphocyte infusion (DLI) to induce remission in those that relapse after allo-HCT. CML, low-grade lymphomas, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) are most susceptible to the GVT effects, whereas acute lymphoblastic leukemia and high-grade lymphomas are relatively resistant. Donor-derived T lymphocytes predominantly mediate GVT reactions, although new evidence supports potential contribution from nonspecific cytokines (host and/or donor derived) and alloreactive natural killer (NK) cells (haploidentical allo-HCT).

Human Leukocyte Antigen Typing

The HLA system consists of a series of cell surface proteins and antigen-presenting cells encoded by the major histocompatibility complex located on chromosome 6 and plays a vital role in immune recognition and function. A striking feature of the HLA system is its enormous diversity. HLA class I molecules include HLA -A, -B, and -C antigens and class II molecules are made up of more than 15 antigens (HLA -DP, -DQ, and -DR). The complexity of the HLA system was revealed with the advent of molecular-based HLA typing, which showed that matched HLA phenotypes by serologic testing (antigen level) were actually diverse when classified by DNA analysis (allele level). The importance of careful HLA matching prior to the selection of a donor cannot be overemphasized and independently impacts graft failure, GVHD, and overall survival (OS). High-resolution HLA typing at the allele level is recommended for all recipients at HLA -A, -B, -C, and -DRB1 at the earliest as it avoids unnecessary delays in identifying a donor. The NMDP recommends rigorous matching at the allele level for HLA -A, -B, -C, and -DRB1 (8/8 match) for adult patients and donors, and a less stringent match for HLA -A and -B (antigen level) and HLA -DRB1 (allele level) for UCB units.

Donor Types for Allogeneic Hematopoietic Cell Transplantation

Related Donor

In the United States, approximately 30% of patients will have an HLA-matched sibling and is the preferred donor source. The probability that a sibling pair is HLA matched is about 25%. The risk of GVHD is higher with increasing HLA disparity, and therefore, most transplant centers prefer a 6/6 or 5/6 HLA match (HLA -A, -B, -DRB1).

Syngeneic Donor

Rarely, an identical twin may serve as the donor. As the donor and recipient are genetically identical, GVHD does not typically occur (rarely noted, when a parous female serves as the donor) and post-HCT immunosuppression is not required. By the same principle, such HCT lacks GVT effects and malignancy relapse rates tend to be significantly higher.

Unrelated Donor

As discussed above the search for an appropriate HLA-matched URD is performed through NMDP. It typically takes 3 to 6 months from the time a suitable donor is located to obtaining the allograft, although this period may be shortened when expedited searches are requested. Seventy percent of Caucasians will have an HLA-identical URD, while it is more difficult for ethnic minorities owing to disparities in registered volunteers in the NMDP registry. The risk of GVHD and graft failure increases with HLA mismatch and NMDP requires at least a 6/8 match prior to approving a match. The presence of recipient HLA antibodies against the mismatched donor HLA molecules in the context of a mismatched URD transplant significantly increased the risk of graft failure. Therefore, recipients of mismatched transplants should be screened for the presence of donor-specific HLA antibodies (DSA). Recent data suggest high-resolution matched URD allo-HCT have similar outcomes to MRD allo-HCT.

Alternative Donors

Include UCB and haploidentical-related donors and have been discussed elsewhere in the chapter.

Donor Evaluation

Careful donor selection and evaluation is an integral part of the pretransplantation workup. The donor must be healthy and able to withstand the apheresis procedure or a bone marrow harvest.

■Donor HLA typing.

■ABO typing.

■History-relevant information of the donor: Any previous malignancy within 5 years, except nonmelanoma skin cancer, is considered an absolute exclusion criterion. Age, sex, and parity of the donor impact HCT outcomes, and though they are not exclusion criteria, younger men and nonparous women are preferred when available. Comorbidities like cardiac or coronary artery disease, lung diseases, back or spine disorders, medications, and complications to general anesthesia should be considered.

■Infection exposure: HIV, human T-lymphotropic virus (HTLV), hepatitis, CMV, HSV, and EBV serology.

■Pregnancy testing for women.

STAGES OF ALLOGENEIC TRANSPLANT

Pretransplant Phase—Conditioning (“The Preparative Regimen”)

This phase of HCT precedes the graft infusion and is characterized by the administration of chemotherapeutic agents +/– radiation. In the conventional sense the goals of the conditioning regimen include immunosuppression of the recipient to prevent graft rejection and to eradicate residual disease. Newer conditioning strategies such as RIC or nonmyeloablative regimens (NMA) preserve immunosuppressive effects to aid donor engraftment with minimal or no myelosuppression.

Myeloablative Conditioning

The most commonly used myeloablative conditioning regimens incorporate high-dose Cy (120 mg/kg) in combination with TBI (usually 12 Gy) or busulfan (Bu). Both regimens are considered equally efficacious, except slight superiority of TBI in acute lymphoid leukemia (ALL). The choice of regimen is guided by factors such as the sensitivity of the malignancy to drugs in the regimen, the toxicities inherent to individual conditioning agents, prior therapies, and age and performance status of the patient. Early regimen-related toxicity includes mucositis, nausea, diarrhea, alopecia, pancytopenia, seizures (Bu), and SOS. Late effects include pulmonary toxicity, hypothyroidism, growth retardation, infertility, an increased risk of cardiovascular disease, and second malignancies (mostly related to TBI).

Nonmyeloablative/Reduced Intensity Conditioning

RIC or nonmyeloablative (NMA) conditioning provides immunosuppression to aid donor engraftment and relies principally on the GVT reactions to eliminate residual malignancy. Cytopenias are limited requiring no or minimal transfusion support. Commonly used truly NMA regimens incorporate fludarabine combined with low-dose TBI (≤2 Gy) or an alkylating agent such as Cy, Bu, or melphalan. While the division is somewhat arbitrary, RIC is intermediate between myeloablative and NMA regimens and is usually associated with cytopenias needing transfusion support. The advent of RIC/NMA regimens has broadened the applicability of allo-HCT to include older patients (>60), and those with poor performance status and comorbidities. Regimen-related toxicity and NRM tend to be less. Unique to RIC/NMA is the presence of assortment of donor and recipient hematopoietic cells in the initial months post-HCT (called mixed chimerism). Several reports indicate that persistent mixed chimerism may lead to higher relapse rates. Immunosuppression withdrawal and less commonly DLI are implemented to convert mixed chimerism by the gradual donor immune–mediated eradication of recipient hematopoietic cells. GVT effects have been observed in several hematologic malignancies, as well as in select metastatic solid tumors such as renal cell carcinoma and neuroblastoma.

Transplant Phase

The transplantation phase is characterized by the intravenous infusion of the graft and usually starts 24 hours after completing the preparative regimen. Infusion is usually well tolerated by the recipient. The day of transplantation is traditionally referred to as “day 0.”

Posttransplant Preengraftment Phase

The early posttransplant phase is characterized by marrow aplasia and pancytopenia. Regimen-related toxicity and infectious complications are common during this phase and usually require intensive support with aggressive hydration, antimicrobial prophylaxis and treatment, GVHD prophylaxis, and transfusion support. All transfused products should be irradiated (to avoid transfusion-associated GVHD) and leukoreduced (CMV safe). Engraftment is the term used to define hematopoietic recovery after HCT. Earliest to occur and sometimes used synonymously with the term engraftment is myeloid engraftment defined as sustained neutrophil count of >0.5×109/L, usually occurring by day +21. Platelet engraftment usually lags behind granulocyte recovery and is usually defined platelet counts of at least >20×109/L without transfusion for 7 days. Erythrocyte engraftment occurs much later and is characterized by independence from PRBC transfusions. Posttransplant cytopenias depend on the conditioning regimen used, diagnosis and disease status, donor source, CD34+ cell dose in the allograft, growth factors, and GVHD prophylaxis.

Posttransplant Postengraftment Phase

Even after myeloid engraftment occurs the recipient remains immunosuppressed due to GVHD prophylaxis/treatment and owing to delayed immune reconstitution, which may take up to 12 months to occur. Notable complications during this phase include infections and GVHD and require continued monitoring. Immunosuppression withdrawal in the absence of GVHD is employed at this stage to facilitate immune reconstitution.

COMPLICATIONS

Figure 30.1 highlights the timeline for some important posttransplant complications after allo-HCT. The following text elaborates the salient features of some key adverse effects and may not be considered comprehensive.

FIGURE 30.1 General timeline of complications after hematopoietic cell transplantation. All complications specific to allogeneic transplantation unless noted by asterisk, in which case they are also seen in autotransplant recipients. GVHD, graft-versus-host disease; RSV, respiratory syncitial virus; SOS, sinusoidal obstruction syndrome; IPS, idiopathic pulmonary syndrome; DAH, diffuse alveolar hemorrhage. (Modified from Cantor AB, Lazarus HM, Laport G. Cellular basis of hematopoiesis and stem cell transplantation. American Society of Hematology—Self Assessment Program. 4th ed. American Society of Hematology; 2010.)

Graft Failure

Graft failure is a rare but serious complication characterized by the lack of engraftment and hematopoietic recovery after allo-HCT. Causes include HLA disparity, recipient alloimmunization, low CD34+ dose, T-cell depletion of the graft, inadequate immunosuppression, disease progression, infections, and medications. Graft failure may be primary (early) when no hematopoietic recovery is noted post-HCT by day +28 or secondary (late) when the initial hematopoietic recovery is lost. Host immune–mediated graft rejection is an important cause of graft failure. Growth factor support, manipulating dosage of immunosuppressive agents, CD34+ stem cell boost, DLI, and regrafting represent important approaches to the management of graft failure.

Infections

Infection remains a major cause of morbidity for patients undergoing HCT. Indwelling catheters are a common source of infections, and bacteremia and sepsis may occur during the neutropenic phase of HCT. Current approaches to minimize the risk of life-threatening infections include the use of prophylactic antimicrobial, antifungal, and antiviral agents, as well as aggressive screening and treatment for common transplantation-associated infections.

Cytomegalovirus

CMV infection most commonly occurs due to reactivation in seropositive patients or rarely because of the transfer of an infection from the donor. The infection usually occurs after engraftment and may coincide with GVHD and/or its treatment. The risk for reactivation is greatest up to day +100. CMV pneumonia and colitis cause significant morbidity and mortality. In addition, it can cause febrile disease, hepatitis, and marrow suppression. Screening for viral reactivation is performed weekly after transplantation by measuring the CMV antigen levels or by polymerase chain reaction (PCR). Initial treatment is with intravenous ganciclovir ± intravenous immunoglobulin. Foscarnet and cidofovir are alternatives (especially in patients with cytopenias). The use of ganciclovir for the initial prophylaxis or preemptive therapy in patients who reactivate CMV posttransplant (i.e., become CMV-PCR+) significantly prevents the development of CMV disease and results in a substantial reduction in CMV-associated morbidity and mortality.

Invasive Fungal Infection

With the routine use of fluconazole prophylaxis in HCT patients, once-lethal invasive Candida infections are relatively uncommon. Other important pathogens include AspergillusFusarium, and Zygomycetes. Common presentations include pneumonia, sinusitis, cellulitis, or fungemia. Patients with GVHD on high-dose steroids are especially at risk for invasive fungal infection and may benefit from expanded selection of antifungal agents.

Others

HSV and VZV reactivation is effectively prevented with acyclovir prophylaxis, but late VZV reactivation after cessation of prophylaxis has been noted. EBV reactivation and posttransplant lymphoproliferative disorders are seen more commonly with T-cell–depleted transplants and in cord blood transplant recipients, especially those who receive antithymocyte globulin (ATG).

Sinusoidal Obstruction Syndrome (Formerly Veno-occlussive Disease)

Hepatic SOS is characterized by jaundice, tender hepatomegaly, and unexplained weight gain or ascites and usually manifests in the first 2 weeks post-HCT. SOS is difficult to treat and typically involves supportive care measures focused on maintaining renal function, coagulation system, and fluid balance. The risk of SOS is higher in combination regimens containing Cy with higher dose TBI or ablative doses of Bu. The intravenous use and pharmacokinetic monitoring of Bu drug levels have dramatically reduced the incidence of SOS. Defibrotide, an investigational agent available through an expanded access trial in the United States for SOS, has shown promising results for treating this order.

Pulmonary Toxicity

Bacterial, viral, or fungal organisms may cause infectious pneumonia. Idiopathic pulmonary syndrome, characterized by fever, diffuse infiltrates, and hypoxia, may occur in 10% to 20% of patients and has an abysmal prognosis in severe cases requiring ventilator support. A subset of patients with diffuse alveolar hemorrhage may respond to high-dose steroids. Use of recombinant factor VIIa has also been reported. Other causes such as CMV pneumonitis, circulatory overload (TACO), and transfusion-associated lung injury (TRALI) must be excluded. Risk factors for pulmonary toxicity include ablative conditioning regimen (TBI), older age, prior radiation, a low DLCO, tobacco use, and GVHD.

Graft-versus-Host Disease

After allo-HCT, donor-derived T lymphocytes may recognize recipient tissue as alien and mount an immunologic attack resulting in GVHD. It is one of the chief treatment-related toxicities and impacts NRM significantly. Conventionally acute GVHD was defined to occur within day +100, and chronic GVHD beyond 100 days posttransplant. It is no longer true and the classification should be based on clinical features rather than time of onset.

Acute GVHD

Up to 50% of MRD allo-HCT can be complicated by acute GVHD. Though varied in clinical presentation, it typically manifests in the first 2 to 6 weeks and affects the skin, liver, and the gastrointestinal system. A commonly used staging system for acute GVHD is presented in Table 30.2. Risk factors for acute GVHD include degree of HLA mismatch, infections (CMV, VZV), URD or haploidentical donors, older patients, multiparous donor, older donors in URD transplants, sex-mismatched transplants (female donor → male recipients), and the use of intensive conditioning regimens.

Prevention of Acute Graft-versus-Host Disease Strategies to prevent acute GVHD have been established and are more effective than treating acute GVHD. Commonly employed strategies include

■Pharmacologic therapy: Combination therapy of nonspecific immunosuppressive agents (methotrexate, steroids) and T-cell–specific immunosuppressant (calcineurin inhibitors—cyclosporine and tacrolimus, mycophenolate mofetil) is preferred to single-agent therapy. Methotrexate IV on days +1, +3, +6, and +11 with tacrolimus or cyclosporine IV/PO starting day –2 is most commonly used. Sirolimus and mycophenolate are sometimes used in lieu of methotrexate. Drug toxicities and interactions are extremely important to monitor and drug levels are followed closely for calcineurin inhibitors and sirolimus.

■T-cell depletion: Achieved by (a) ex vivo separation by CD34+ selection or the use of monoclonal antibodies to remove T cells or (b) in vivo T-cell depletion with the use of monoclonal antibodies such as ATG or alemtuzumab or the administration of posttransplant Cy. Though effective in reducing GVHD, these maneuvers may increase relapse rates and infections due to late immune reconstitution.

Treatment of Acute Graft-versus-Host Disease Frontline treatment for clinically significant (grades II–IV) acute GVHD is methylprednisolone at a dose of 2 mg/kg/day and calcineurin inhibitors should be continued or restarted. For those not responding or with partial response mycophenolate is usually added. Additional agents (azathioprine, daclizumab, photopheresis, ATG, infliximab) are used with variable success. Steroid refractory acute GVHD portends very poor prognosis. Prophylactic antifungal therapy against Aspergillus should be considered in those on corticosteroid treatment.

Chronic GVHD

Use of PBPC allografts, URD, and prior history of acute GVHD are risk factors. It presents with variable and multisystem organ involvement, and clinical manifestations may resemble autoimmune disorders (i.e., lichenoid skin changes, sicca syndrome, scleroderma-like skin changes, chronic hepatitis, and bronchiolitis obliterans). Chronic GVHD is often accompanied by cytopenias and immunodeficiency. Treatment involves prolonged courses of steroids and other immunosuppressive agents as well as prophylactic antibiotics (e.g., penicillin) and antifungal agents. Other potentially useful agents include thalidomide, mycophenolate mofetil, imatinib mesylate, pentostatin, rituximab, photopheresis, Psoralen ultraviolet radiation (skin GVHD), and possibly interleukin-2 administration.

Relapse

Relapse after allo-HCT is ominous, especially for aggressive malignancies such as AML and ALL. Most relapses occur within 2 years of transplantation, and those that relapse within 6 months have the worst prognosis. Immunosuppression is typically withdrawn to enhance the GVT effect and, in some cases, DLI is administered. This frequently results in GVHD. The most favorable responses to DLI have been seen in patients with CML, especially those with molecular or chronic phase relapse. Second transplant for relapsed disease rarely results in long-term disease-free survival and is associated with a very high risk of NRM.

SURVIVORSHIP

It is estimated that there are over 125,000 patients who are long-term (>5 years) survivors after HCT. While survivors after auto-HCT lead near-normal lives, studies have consistently shown that allograft recipients have lower life expectancy than age-matched population. Long-term complications depend on the conditioning regimen, age, and presence of chronic GVHD. Some key points are as follows:

■Auto-HCT survivors are at risk for lung dysfunction, cardiovascular diseases, and secondary myelodysplasia/AML.

■Major complications afflicting allo-HCT survivors include chronic GVHD; infections; organ dysfunction involving pulmonary, cardiovascular, endocrine, and immune systems; secondary myelodysplasia/AML; and solid organ malignancies. In addition, the pediatric population is at risk for growth retardation.

■Immunizations are recommended for auto-HCT patients at 1 year and after withdrawal of immunosuppressive agents for allo-HCT. Long-term antibiotic prophylaxis is needed for patients receiving prolonged treatment for chronic GVHD.

■Recommended screening and preventive measures for survivors have been established (see the reference list). This includes routine hemogram, hepatic, and renal function tests, endocrine screening (lipid panel, vitamin D, and thyroid panel), immunologic studies, and other studies (echocardiogram, pulmonary function tests, age-appropriate cancer screening, ophthalmologic evaluation, and bone densitometry).

CONCLUSION

HCT has evolved into an effective therapeutic option for a broad range of disease entities. The improved safety profile of the procedure and the increasing availability of donor sources have led to an increase in the number of transplants performed each year. There have been improvements in survival, less acute complications, and improved awareness and treatment of chronic complications. The number of patients who benefit from this procedure will likely increase as future transplantation strategies continue to evolve, minimizing adverse effects and expanding the stem cell source, while maximizing the beneficial effects donor immune–mediated GVT effects.

REVIEW QUESTIONS

1.A 36-year-old Caucasian female with no siblings was diagnosed with AML with normal cytogenetics. She received standard “3 + 7” induction chemotherapy and entered complete remission and completed four cycles of consolidation therapy. Six months later she presents with peripheral blasts and bone marrow evaluation confirms relapse. Apart from admitting the patient for reinduction chemotherapy and supportive care, what other step should be initiated at this time?

A.Consider high-dose therapy and autologous HCT.

B.HLA type the patient and run a preliminary search for URD allogeneic HCT.

C.HLA type the patient, but defer allogeneic HCT for next relapse.

D.Do nothing; allogeneic HCT is not a treatment option for this patient.

2.A 55-year-old male with relapsed Hodgkin lymphoma underwent high-dose therapy with BEAM (carmustine + etoposide + cytarabine + melphalan) followed by autologous PBPC infusion. Hematopoietic recovery occurred by day +14 and he was discharged from the transplant center by day +25. He reports to your clinic on day +48 with 3-day onset of progressive dyspnea and dry cough. His current medications include trimethoprim-sulfamethoxazole and acyclovir. On examination his pulse is 110, BP 108/70, respiratory rate 34, and pulse-oximetry reads 88% on room air. Chest x-ray shows nonspecific interstitial markings. What should be the next step in his management?

A.Initiate the patient on intravenous azithromycin and ceftriaxone.

B.Stop trimethoprim-sulfamethoxazole and start the patient on inhaled pentamidine.

C.Start IV ganciclovir and immunoglobulin.

D.Obtain a pulmonary function test and start the patient on steroid therapy.

3.You are evaluating the 40-year-old HLA-matched brother of a patient with AML with complex cytogenetics in CR1. The potential donor is in good health, has no medical complaints, and is not on any medications except a history of basal cell carcinoma that was resected 3 years ago. When counseling the patient regarding PBPC collection, which of the following statements is accurate?

A.The history of basal cell carcinoma rules him out as a donor for allogeneic HCT.

B.The procedure consists of giving a single-dose Cy followed by growth factors for mobilization and progenitor cell collection by apheresis.

C.The procedure is well tolerated with the most common side effect being self-limiting bone pain and a very rare risk of splenic rupture.

D.The history of AML in his sibling (recipient) increases significantly the risk of future AML in the brother and so he cannot serve as a donor.

4.A 50-year-old woman with history of CML underwent mismatched URD PBPC allogeneic HCT 16 days ago after Cy and Bu conditioning. She had myeloid engraftment on day +12. She complains of diffuse abdominal pain that is more prominent in the right upper quadrant. Her stool output is documented as 150 mL of liquid stool over the last 24 hours. Volume status shows that she is 3 L positive with a weight gain of 2.5 kg compared to the day before. Blood work shows hyperbilirubinemia (3 mg/dL), stable hemogram, creatinine 1.1, and normal peripheral smear. What is the most likely diagnosis?

A.SOS

B.Acute GVHD

C.Hepato-splenic candidiasis

D.Thrombotic microangiopathy

Suggested Readings

1.Alousi AM, Bolaños-Meade J, Lee SJ. Graft-versus-host disease: the state of the science. Biology of Blood and Marrow Transplantation. Available at: http://www.sciencedirect.com/science/article/pii/S1083879112004582

2.Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487-1496.

3.Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282-288.

4.Cantor AB, Lazarus HM, Laport G. Cellular basis of hematopoiesis and stem cell transplantation. Stephanie A. Gregory, Keith R. McCrae, eds. In: American Society of Hematology—Self Assessment Program. 3rd ed. American Society of Hematology, Washington DC; 2010.

5.Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17):1813-1826.

6.Hamadani M, Craig M, Awan FT, Devine SM. How we approach patient evaluation for hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(8):1259-1268.

7.Horowitz MM, Confer DL. Evaluation of hematopoietic stem cell donors. ASH Education Program Book. 2005;2005(1):469-475.

8.Lowsky R, Negrin RS. Principles of hematopoietic cell transplantation. In: Kenneth Kaushansky, Marshall Lichtman, E. Beutler, Thomas Kipps, Josef Prchal, Uri Seligsohn eds. Williams Hematology. 8th ed. The McGraw-Hill Companies; New York. 2008.

9.Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18(3):348-371.

Invaluable Web Resources for Further Reading

10.American Society of Blood and Marrow Transplantation. www.asbmt.org

11.Center for International Blood and Marrow Transplantation. www.cibmtr.org

12.National Marrow Donor Program. www.marrow.org



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